tbuckley/cabot-search huggingface dataset:
Clinical utility of an international multidisciplinary virtual tumor board for fibrolamellar carcinoma.
Authors: Paul Kent, Jordan C. Tasse, Erik Schadde, Tomoaki Kato, Abhinav Humar, Oliver M. Fisher, Matthew Dixon, Darrell Yamashiro, Albert Cornelius, Nelson Andrew Royall, Thomas Kim, Julie C. Friedland, Timothy Joseph Stuhlmiller, Alaa Awawda, Alanis Sabates, Mark Adam Shapiro, Jessica Ellison, Tom Stockwell
Journal: Journal of Clinical Oncology (2023)

e18624 Background: Fibrolamellar carcinoma (FLC) is a rare liver cancer with approximately 1500 new cases per year, worldwide. The lack of expertise locally often incurs significant travel for patients (pts). Virtual consults have improved access to expertise but identifying the best experts for an ultra-rare condition is difficult for pts and families and multidisciplinary tumor boards of experts offer better clinical guidance. Foundations and advocacy groups play a vital role in navigation and support for pts with rare cancers. Methods: Pts with FLC and their local treating oncologists were engaged by the FibroFighters Foundation and offered a multidisciplinary virtual tumor board (VTB) review. Each VTB included the local treating oncologist, a patient advocate, a molecular pharmacologist, and international experts in the clinical management of FLC including at least one medical oncologist, one radiation oncologist, one interventional radiologist, and one surgical oncologist. Each VTB reviewed the pts’ clinical history and relevant imaging and discussed surgical, radiological, and systemic approaches. Pts consented to the observational research protocol XCELSIOR ( NCT03793088 ) to enable longitudinal clinical summaries to be prepared and for outcomes to be annotated. Results: Between August 4 th 2022 and February 9 th , 2023, the VTB held a total of 71 discussions for 59 unique pts (12 discussed more than once): 12 new diagnoses, 28 relapses, 14 treatment failures, and 5 ongoing care. Median age at diagnosis of pts was 18 years (range 6-44 years). Pts were seen at 44 institutions/practices across 22 states and 4 countries (USA, Australia, Switzerland, and the Netherlands). A total of 36 unique treatment regimens were discussed, with 21 unique consensus top-ranked options delivered to treating oncologists. The most common consensus options included regimens of gemcitabine, lenvatinib, and nivolumab (13), interventional radiology (IR, 11), surgical resection (6), and a regimen of gemcitabine, oxaliplatin, and lenvatinib (6). The primary team implemented the VTB recommendations 60 times out of 71 (85%): change in systemic therapy (33), IR (11), continue current regimen (11), surgery (6), radiation oncology (2). Conclusions: This is the first demonstration of a patient-focused international multidisciplinary VTB for FLC. The high rate of recommendation adoption by local treating oncologists suggests this is a valuable service to improve patient care. Outcomes are being collected prospectively in a master observational research protocol to better define clinical utility.
m6A mediated upregulation of lncRNA CASC9 in head and neck squamous cell carcinoma.
Authors: Noushad Karuvantevida, Paramasivam Arumugam
Journal: Journal of Clinical Oncology (2023)

e15165 Background: Long noncoding RNAs (lncRNAs) are dysregulated in many cancers including head and neck squamous cell carcinoma (HNSCC). Many recent studies have shown that abnormal expression of lncRNA CASC9 (CASC9) is involved in the pathophysiological processes of cancers. N6-methyladenosine (m6A) represents the most common methylation modification of lncRNAs and has been shown to play important roles in the development of different cancer types. However, the potential role of m6A mediated upregulation of CASC9 in HNSCC and its molecular mechanisms remain largely unknown. In the present study, we identified the molecular mechanisms of CASC9 in promoting the malignancy of HNSCC. Methods: We used real-time polymerase chain reaction (qPCR) to identify the level of CASC9 expression in HNSCC clinical samples and cell lines. The oncogenic role of CASC9 in HNSCC was analyzed using online tool UALCAN. RNA immunoprecipitation sequencing (MeRIP-seq) was performed to determine the m6A modification of CASC9. The relationship between CASC9 expression and patients prognosis was analysed using Kaplan-Meier plotter. Loss of function studies used to evaluate cell proliferation, viability, and migration of HNSCC cell lines. Results: Results revealed that m6A mediated CASC9 expression was significantly upregulated in HNSCC tissues than those in the paired adjacent non-tumor tissues. Similarly, m6A mediated CASC9 was significantly overexpressed in the HNSCC cell lines compared with normal cells. The upregulated CASC9 expression was significantly associated with advanced stages and closely correlated to the unfavorable prognosis. m6A was highly enriched within CASC9 and enhanced its RNA stability. Knockdown of CASC9 remarkably inhibited the proliferation, migration and promoted the apoptosis of HNSCC cells. Mechanistically, we found that IGF2BP2 (insulin-like growth factor 2 mRNA binding protein 2), m6A reader could recognize the m6A site in CASC9 and enhance its stability. Conclusions: Overall, this work highlights for the first time that m6A modification enhance CASC9 stability may serve as a potential prognostic biomarker and therapeutic target in HNSCC.
Peri Cruiser CAR-T: An innovative platform to reduce on-target off-tumor toxicity of CAR-T therapy.
Authors: shuangshuang zhang, Ruidong Hao, Hongye Wang, Qiao yong Yi, Li Yantao, Yunpeng Zhong, Minmin Sun
Journal: Journal of Clinical Oncology (2023)

2539 Background: On-target off-tumor toxicity is a significant concern in Chimeric Antigen Receptor (CAR)-T therapies, especially for solid tumors, leading to adverse effects on normal tissues and impacting on treatment efficacy. To address this challenge, a modified form of CAR-T cells named Peri Cruiser CAR-T has been developed by using miRNA technology to knock down three adhesion genes that mediate T cell transendothelial migration to normal tissues, aiming to block the extravasation of CAR-T cells so that the on-target off-tumor toxicity could be prevented without compromising anti-tumor efficacy. In this study, we provided a proof of concept by using the epithelial cell adhesion molecule (EpCAM) as a targeting tumor-associated antigen (TAA). Methods: An miRNA cassette was incorporated into the vectors of anti-human or mouse EpCAM CARs. The knockdown efficiency, endothelial adhesion efficiency, effector functions and memory phenotypes in vitro were evaluated. To determine the toxicity in vivo, the anti-mouse EpCAM CAR-T cells were administered to non-tumor bearing NSG mice, and the body weight and T cell infiltration in normal tissues was evaluated. Anti-tumor efficacy was also evaluated in NSG mice with subcutaneous and metastatic tumor models by anti-human EpCAM CAR-T cells. Results: Our Peri Cruiser CAR-T platform was capable to effectively downregulate the target genes by 10 folds. The knockdown is stable after extended culture and antigen engagement in vitro. This knockdown of targeted genes significantly decreased T cell adhesion to endothelial cells and corresponding ligands, but did not affect T cell activation or effector functions such as cytotoxicity and IFN gamma release. Surprisingly, lowering the levels of these adhesion molecules improved the memory phenotypes of CAR-T cells as indicated by increased portion of CCR7+CD45RO+ cells. In vivo studies showed that conventional EpCAM CAR-T-injected mice experienced severe weight loss and all had to be sacrificed before day 8, the IHC staining of CD3 revealing massive infiltration of T cells in lung, liver, and kidney. However, the incorporation of the miRNA cassette prevented T cell infiltration in normal tissues, reversed the toxicity, and ensured the survival of all mice. The anti-tumor efficacy of these T cells was evaluated in vivo and found to decrease metastasis as effectively as the conventional CAR-T cells in a metastasis model of HCT116-Luc, although there was a slightly but not significantly decreased efficacy in a subcutaneous model of HCT116. Conclusions: The Peri Cruiser CAR-T platform can significantly improve the safety of CAR-T cells without compromising their efficacy to eliminate tumor cells in primary site and metastasis. This technology opens another avenue to safely target a variety of other TAA by CAR-T even when there is the potential of on-target off-tumor toxicity in normal tissues for those antigens.
X-linked inhibitor of apoptosis protein (XIAP) expression level analyzed by immunohistochemistry (IHC) as it relates to clinical and pathologic characteristics in prostate cancer.
Authors: Jennifer Kate Beckerman, Claire Valburg, Ramesh Subrahmanyam, Victor Nava, Alexandra Zara Rozalen, Guoqing Diao, Shanshan Liu, Martha Antonio, Maneesh Rajiv Jain
Journal: Journal of Clinical Oncology (2023)

e17012 Background: XIAP acts in both the extrinsic and intrinsic apoptotic pathways as an inhibitor of cell death, protecting cells from a range of triggers. Regulation due to apoptosis resistance may represent a targetable factor for therapeutic intervention in prostate cancer. This study focuses on XIAP as a biomarker and its expression in correlation with disease aggression. Methods: Expression levels of XIAP was analyzed by immunohistochemistry (IHC), graded 1 through 3 according to signal intensity, in radical prostatectomy samples from 90 patients with prostate cancer with a range of phenotypes including: indolent (A), locally advanced (B), progressive to metastatic (C) and de novo metastatic (D). Prognostic data was collected and Fisher’s exact statistical analysis was performed. Secondary analyses included a Fisher’s exact test with a pairwise comparison between individual disease grades and Gleason scores. Results: Higher XIAP protein expression levels on IHC correlated with disease grade and with total Gleason score (p = 0.0008 and p = 0.0002 respectively) by Fisher’s exact test analysis, indicating more aggressive disease phenotypes. Secondary results looked at a pairwise Fisher’s exact analysis comparing XIAP expression levels among disease grades (A-D) and Gleason scores. XIAP expression only significantly differed between those with grade A and D as well as between individuals with grades B and D (measured by Bonferroni-adjusted p-value of 0.003 and 0.018 respectively). Statistical significance was also achieved in XIAP expression levels when comparing among Gleason scores 6 and 8 (p = 0.025), 6 and 9 (p = 0.0125), as well as 7 and 9 (p = 0.030). Conclusions: This study demonstrates a correlation between XIAP expression levels by IHC and aggressiveness of disease, demonstrating clinical significance of XIAP as a prostate cancer biomarker. [Table: see text]
High-dose vitamin C to enhance neoadjuvant immune checkpoint therapy in mismatch repair proficient colon cancer: The ALFEO pilot study.
Authors: Andrea Sartore-Bianchi, Alessio Amatu, Federica Di Nicolantonio, Teresa Troiani, Federica Tosi, Stefania Napolitano, Giulia Martini, Katia Bencardino, Erica Bonazzina, Pietro Carnevali, Edoardo Forti, Massimo Mutignani, Angelo Vanzulli, Silvia Ghezzi, Francesco Scaglione, Silvia Marsoni, Alberto Bardelli, Fortunato Ciardiello, Giovanni Ferrari, Salvatore Siena
Journal: Journal of Clinical Oncology (2023)

TPS2675 Background: Most colon cancer (CC) patients can be treated with upfront curative surgery; however, relapse often occurs and the disease becomes deadly. Neoadjuvant chemotherapy does not jeopardize timing or quality of surgery and enhances relapse-free outcomes in proficient mismatch-repair (pMMR) CC (Morton et al, J Clin Oncol 2023). In the same setting, the use of immune checkpoint inhibitors (ICIs) with a single dose of ipilimumab (Ipi) and two doses of nivolumab (Nivo) proved to be feasible without delaying surgery and resulting in 23% major pathological responses (mPR) (Chalabi et al, ASCO 2022). We have previously shown that high dose vitamin C (HDVitC) triggers tumor infiltration and activation of CD8+ T cells in mouse tumors, enhancing efficacy of ICIs in pMMR CC preclinical models (Magrì et al, Sci Transl Med 2020). Methods: ALFEO is an open-label pilot trial of neoadjuvant CC treatment to test whether HDVitC can enhance the efficacy of ICIs in this setting. Main inclusion criteria are pMMR CC stage cT4N0/TxN1-2/[cM1 liver-limited disease with favorable oncological criteria candidate for upfront surgery on both T and M after multidisciplinary team evaluation]. Patients will receive Nivo i.v. 3 mg/kg D1 and D15, Ipi i.v. 1 mg/kg D 1 and VitC 70 g/ m 2 D1-3 and 15-17. Tumor assessment will be performed at D21-28, followed by surgery within D28. Primary objective is activity of Nivo/Ipi + HDVitC; secondary objective is safety; exploratory objectives are correlation between efficacy and pharmacodynamic including tumor microenvironment changes. Primary endpoint is mPR rate. Considering the proof-of-principle nature of the trial, a design with a boundary for early stopping (both futility/utility and toxicity) and a fixed maximum sample size of 24 patients has been chosen. mPR for the Ipi/Nivo has been set at 23% (H 0 ), while H 1 at 75%. A Bayesian hypothesis test-based design (Zhou et al, Pharm Stat 2021) will be used for decision-making. Su. Clinical trial information: ECTR2022-502101-15-00 .
Factors associated with myocarditis in patients with cancer treated with immune checkpoint inhibitors.
Authors: Zara Izadi, Yan Zhang, Youbei Lou, Brian Dreyfus, Greg Plautz, Robert Wolf, Leslie Cooper
Journal: Journal of Clinical Oncology (2023)

e14674 Background: Myocarditis is an uncommon but serious adverse event (AE) of immune checkpoint inhibitor (ICI) therapy. We aimed to identify factors associated with ICI-related myocarditis in cancer patients using pooled data from multiple clinical trials. Methods: Data on 25,965 adults receiving at least one dose of an ICI (nivolumab [NIVO] or ipilimumab [IPI])-containing regimen were extracted from corporate safety and clinical trial databases. Patients missing documentation of AEs, indication, or trial ID were excluded. Myocarditis events were identified using MedDRA preferred terms. A nested case-control study design with controls who had no myocarditis selected at random from the risk sets and matched 1:5 on ICI regimen, duration of exposure to ICI regimen, and trial ID was used. Descriptive statistics were used to derive time to onset of myocarditis and to investigate patterns of myositis and rhabdomyolysis relative to myocarditis. A multivariable conditional logistic regression model was used to identify factors associated with myocarditis. Covariates included age, sex, race/ethnicity, medical history (cardiovascular disease, diabetes, sleep apnea), smoking, cancer type, medication use (within the prior 6 months), and co-occurrences of other AEs (pneumonitis, colitis, and hepatitis). Results: Myocarditis was documented in 122/24,106 (0.5%) patients meeting study eligibility criteria. A total of 732 patients (122 cases and 610 matched controls) from 46 trials were included in the analyses. Mean (SD) age was 63 (12) years; 65% of patients were male, 76% Caucasian, and 52% had a history of cardiovascular disease. NIVO + IPI was the most commonly used regimen (36%), followed by NIVO + relatlimab (25%) and NIVO + chemotherapy (14%). Median (Q1-Q3) time to onset of myocarditis was 38 (26-77) days from first dose of ICI. Myositis was reported in 18/122 (15%) cases and in 2/610 (0.3%) controls (p&lt;0.001). Among the 18 cases, a majority (83%) developed myositis within 3 days before the onset of myocarditis. Rhabdomyolysis was reported in 4/122 (3%) cases, all within a month before myocarditis, and in none of the controls (p=0.001). In adjusted analyses, older age (odds ratio 1.38 per 10-year increase, 95% CI 1.12-1.70) and hepatitis (5.69, 2.24-14.44) were significantly associated with the development of myocarditis. Conclusions: In this large cohort of ICI-treated cancer patients, myocarditis had an early onset and was associated with older age and co-occurrences of hepatitis. Due to a low incidence among controls, rhabdomyolysis and myositis could not be included as covariates in adjusted analyses; however bivariate results showed strong associations between myocarditis and rhabdomyolysis or myositis. These findings suggest that co-occurrences of myositis, rhabdomyolysis, or hepatitis are associated with myocarditis and may originate from a more generalized ICI myopathy.
Development of a CUB domain-containing protein 1 (CDCP1)-targeting antibody-drug conjugate for triple-negative and metastatic breast cancer.
Authors: Madeline Gough, Kayden Kwah, Yaowu He, Cameron Edward Snell, John D. Hooper, Thomas Kryza
Journal: Journal of Clinical Oncology (2023)

e15012 Background: CUB-domain containing- protein 1 (CDCP1) is a transmembrane receptor involved in the progression of several cancers. Recent studies demonstrate that CDCP1 is a rational target for the development of innovative targeted therapies for cancer including theranostics agents and antibody-drug conjugates. Methods: To determine the therapeutic potential of CDCP1 in breast cancer, we investigated its expression in multiple cohorts of breast cancer tissues by immunohistochemistry, as well as in various preclinical models including cell lines, primary cells and patient-derived xenografts using flow cytometry, western blot and immunofluorescence staining. Then, we evaluated the capacity of the CDCP1-targeting chimeric antibody ch10D7 to specifically accumulate in breast cancer lesions in in vivo preclinical models including patient-derived xenografts and breast cancer metastasis models. Finally, we determined the efficacy of the ch10D7-MMAE antibody-drug conjugate to kill breast cancer cells in vitro and breast tumours ex-vivo and in vivo. Results: The CDCP1 receptor is expressed at targetable level in a significant proportion of breast cancer cases with high/intermediate expression detected in ~30% of localized ER-positive cases, ~50% of metastatic ER-positive cases and &gt; 70% of Triple-negative or HER2-positive cases. Similar proportion of expression was detected in cellular models. We demonstrated that ch10D7 antibody labelled with the radionucleotide Zircodium-89 specifically accumulates in breast cancer lesions in vivo allowing the detection of mammary-fat pad implanted patient-derived xenografts and of breast cancer metastasis by PET/CT imaging. Finally, we confirmed that the ch10D7-MMAE antibody-drug conjugate is very efficient at inducing cell death in vitro as well as controlling primary tumour and metastatic tumour burden in pre-clinical models, conferring a significant survival advantage compared to classical therapy. Conclusions: Our work demonstrates that CDCP1 is a potential target to detect and limit the progression of breast tumours in both the primary and metastatic disease setting, particularly in triple-negative and HER2-positive breast cancer subtypes. Furthermore, we show that biomolecules specifically recognising this receptor are promising therapeutic agents which could improve survival of patients.
A retrospective study of the efficacy and safety of donafenib combined with TACE as adjuvant therapy in patients with high-risk recurrence factors after hepatocellular carcinoma surgery.
Authors: Qifei Zou, Shengxian Yuan
Journal: Journal of Clinical Oncology (2023)

e16121 Background: Surgical resection is the most important treatment for patients with hepatocellular carcinoma (HCC) to obtain long-term survival. However, the 5-year recurrence rate after hepatectomy is as high as 40%-60% and above. Reducing the postoperative recurrence rate is the key to improve the overall efficacy of HCC. This study aimed to evaluate the efficacy and safety of donafenib combined with TACE as adjuvant therapy in HCC patients with high-risk recurrence factors after surgical resection. Methods: This single-center retrospective study enrolled primary HCC patients with high-risk recurrence factors who underwent surgical resection at Shanghai Eastern Hepatobiliary Surgery Hospital from April 2021 to October 2022. High-risk recurrence factors included: the number of tumors ≥ 3, tumor diameter ≥ 5 cm, portal vein tumor thrombus, microvascular invasion (MVI) and satellite lesions. Patients received adjuvant therapy of donafenib combined with TACE after surgery. Patients’ demographic characteristics, etiological characteristics, 1-year recurrence-free survival rate (RFSR), recurrence-free survival (RFS), overall survival (OS), and treatment-related safety were analyzed. Results: A total of 40 patients were enrolled with a median age of 55.5 years (21-78), 39 patients (97.5%) in BCLC stage B and 1 patient (2.5%) in BCLC stage C. 33 patients (82.5%) were co-infected with HBV. All 40 patients had ECOG PS scores of 0 and Child-Pugh scores of A. A total of 34 patients (85%) with MVI were pathologically reported after surgery, 23 patients (57.5%) with tumor diameter ≥5cm, 9 patients (22.5%) with portal vein cancer thrombus, and 6 patients (15%) with satellite lesions. All patients received at least one TACE treatment after surgery, 31 patients (77.5%) received the TACE treatment one month after surgery, and 9 patients (22.5%) received the TACE treatment within one month after surgery. The initial dose of donafenib was 200mg/day. As of the cut-off date of data collection, the median follow-up time was 9 months (95%CI: 7.73-10.27), 4 patients relapsed and 2 patients died. The median RFS was 18 months (95% CI: 13.673-22.327), the one-year RFSR was 83.3% (95% CI: 61.9%-93.8%), and the one-year OS rate was 95.8% (95% CI: 75.2%-99.6%). 21 patients (52.5%) had combined treatment-related adverse events (TRAE), of which 4 patients (10%) had Grade 3 TRAE and no grade 4 or 5 TRAE were reported. Common adverse events included hand-foot skin reaction (9 patients, 22.5%), diarrhea (9 patients, 22.5%), rash (5 patients, 12.5%), hypertension, and gastrointestinal reactions (2 patients each, 5%). Conclusions: Donafenib combined with TACE was used for adjuvant therapy in patients with high-risk recurrence of HCC, which has a high one-year recurrence-free survival rate and was well tolerated.